chr11-17593282-C-T

Variant names:

• chr11-17593282-C-T
• rs75133799
• NM_001292063.2:c.3096C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001277269.2(OTOG):​c.3132C>T​(p.Asn1044Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,550,482 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (7 hom., cov: 33)
  • Exomes 𝑓: 0.013 (135 hom.)
• Consequence: OTOG NM_001277269.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.85
• Publications: 1 publications found

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-17593282-C-T is Benign according to our data. Variant chr11-17593282-C-T is described in ClinVar as Benign. ClinVar VariationId is 226878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00927 (1412/152308) while in subpopulation NFE AF = 0.0153 (1043/68026). AF 95% confidence interval is 0.0146. There are 7 homozygotes in GnomAd4. There are 662 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277269.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.3096C>T	p.Asn1032Asn	synonymous	Exon 26 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.3132C>T	p.Asn1044Asn	synonymous	Exon 25 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.3096C>T	p.Asn1032Asn	synonymous	Exon 26 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.3132C>T	p.Asn1044Asn	synonymous	Exon 25 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.461C>T		non_coding_transcript_exon	Exon 3 of 22

Frequencies

GnomAD3 genomes AF: 0.00928 AC: 1412 AN: 152190 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00978 AC: 1459 AN: 149248 AF XY: 0.0102

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00635

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0000927

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0127 AC: 17807 AN: 1398174 Hom.: 135 Cov.: 31 AF XY: 0.0127 AC XY: 8728 AN XY: 689618

African (AFR) AF: 0.00215 AC: 68 AN: 31592

American (AMR) AF: 0.00770 AC: 275 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 497 AN: 25180

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35738

South Asian (SAS) AF: 0.00641 AC: 508 AN: 79234

European-Finnish (FIN) AF: 0.00309 AC: 149 AN: 48170

Middle Eastern (MID) AF: 0.0253 AC: 144 AN: 5698

European-Non Finnish (NFE) AF: 0.0143 AC: 15414 AN: 1078866

Other (OTH) AF: 0.0129 AC: 750 AN: 57994

GnomAD4 genome AF: 0.00927 AC: 1412 AN: 152308 Hom.: 7 Cov.: 33 AF XY: 0.00889 AC XY: 662 AN XY: 74484

African (AFR) AF: 0.00272 AC: 113 AN: 41564

American (AMR) AF: 0.00837 AC: 128 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1043 AN: 68026

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.0135 Hom.: 7

Bravo AF: 0.0100

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.45
DANN	Benign	0.70
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75133799; hg19: chr11-17614829; COSMIC: COSV61127745;